Background:

Colorectal cancer (CRC) remains a major global health challenge due to the limitations of current therapies, including systemic toxicity and inadequate tumor specificity. Natural products like nutmeg (Myristica fragrans) exhibit anticancer potential, but their clinical application is limited by poor bioavailability. Integrating nutmeg extracts into nanocarriers may overcome these barriers and enhance their therapeutic efficacy.

Methods:

Nutmeg extract was prepared using supercritical CO₂ extraction (NSFE) and encapsulated into hybrid poly(lactic-co-glycolic acid)–lipid nanoparticles (NSFE-PLGA-LN) via nanoprecipitation. Characterization included particle size (DLS), morphology (TEM), zeta potential, and encapsulation efficiency. Metabolomic profiling was performed using UHPLC-HRMS/MS. Bioactivity was predicted through network pharmacology and molecular docking against CRC-related targets (EGFR, PTGS2, STAT3, JAK2, PIK3CB). Cytotoxic effects were assessed in CRC cell lines (HT-29, HCT-116) and normal colon fibroblasts (CCD-18Co) using MTT assays.

Results:

Metabolomic analysis identified bioactive compounds including myristicin, elemicin, β-caryophyllene, and sabinene. Network pharmacology and docking simulations revealed significant interactions with CRC-related pathways, notably apoptosis, proliferation, and inflammation, with β-caryophyllene demonstrating strong affinity (Vina score ≤ –7.2 kcal/mol). NSFE-PLGA-LN exhibited selective cytotoxicity, with IC₅₀ values of 95.5 µg/mL (HT-29), 89.2 µg/mL (HCT-116), and minimal toxicity on normal CCD-18Co cells (IC₅₀=896.5 µg/mL).

Conclusions:

Hybrid PLGA–lipid nanoparticles significantly enhanced nutmeg extract’s therapeutic profile, providing selective, sustained anticancer activity. These findings support further preclinical evaluation and mechanistic studies warranted for potential clinical translation.